Summary Despite recent advances, heart failure (HF) continues to be the leading cause of death in the U.S., and the rest of the western world. Approximately 37% of myocardial infarction (MI) patients will die from HF within 1 year, and of those who do survive, two-thirds do not make a complete recovery. Each year it is estimated that ~550K Americans will have a new MI, and ~200K will have a recurrent MI, leading to a large body of patients suffering from HF. Therefore, our long-term goal is the development of new, minimally invasive, targeted biomaterial based therapies for the treatment of acute MI (AMI), thereby limiting the number of patients that progress to HF. Recently there has been significant progress in the development injectable biomaterials that stimulate endogenous repair on their own or through the controlled release of additional therapeutics. This approach is attractive since potential therapies could be delivered minimally invasively via catheter, would be off the shelf and cost-effective, and in the case of therapeutic delivery, would provide targeted delivery limiting systemic off- target effects that plague traditional pharmaceuticals. However, the approach of direct injection of these biomaterials (either through minimally invasive surgery or percutaneous transendocardial injection) is unlikely to be translated to AMI patients because of serious safety concerns with the injection procedures, thereby missing the critical therapeutic window immediately post-MI. Together, the PIs have developed a new biomaterials based approach for delivering therapeutics that would obviate the need for direct injection into the heart, which could enable intracoronary infusion, a procedure that is possible at the time of MI, or even less invasive intravenous (IV) injection. This approach involves the use of enzyme-responsive peptide-polymer amphiphilic nanoparticles, which respond to matrix metalloproteineases (MMP-2 and MMP-9) that are upregulated in heart post-MI. The nanoparticles undergo a morphological transition from nanoscale spherical- shaped, discrete materials to scaffold like, micron scale assemblies when acted upon by MMPs at the site of MI. While our previous work demonstrated proof-of-concept for the use of MMP-responsive nanoparticles for the targeted delivery and retention in an AMI, the polymeric nanoparticles were non-degradable, which would limit translation, and did not carry a therapeutic cargo. Here, we aim to develop translatable, degradable systems as well as demonstrate proof-of-concept for using this novel biomaterial platform for the targeted delivery of therapeutics for AMI. !